THE EFFECT OF BROMPHENIRAMINE ON COUGH SENSITIVITY IN HEALTHY VOLUNTEERS

Haytham M. El-Khushman MD*

ABSTRACT

Objective: To evaluate the anti-tussive effect of brompheniramine maleate a non-selective, sedative antihistamine using capsaicin challenge. Methods: Twelve subjects, five females and seven females, mean age 32 years with a range of (23-39) years, were studied on two occasions. On the two visits a baseline capsaicin dose-response was performed to determine C5 (the lowest concentration causing 5 coughs). After 30 minutes two C5 doses of capsaicin were given and the total cough over one minute was counted. On the first visit Brompheniramine 8mg or a matched placebo was given orally, and 120, 240 minutes after administration, two C5 doses of capsaicin were given and the total coughs over one minute period were counted. This was repeated exactly in the second visit except subjects received either a placebo or active treatment; either which they had not received on their first visit. Subjects were also asked to quantify their drowsiness using a 100 mm visual analogue scale. Results: Baseline mean cough number (confidence interval) was similar on the two study occasions 9.9 (8.2-11.7) before Brompheniramine and 9.2 (7.3-11.1) before placebo. Cough number did not differ on the two study days at 120 and 240 min after Brompheniramine treatment: 7.7 (5.5-9.8), 7.4 (5.1-9.6) compared to 8.7 (6.4-11.0), 8.3 (6.8- 9.8) after placebo. Mean visual analogue scale (confidence interval) after Brompheniramine was 31 (14-48) and 40 (21-60) compared to 7 (2-12) and 7 (2-12) after Placebo at 120 and 240 min respectively (p<0.008). Conclusion: The sedative anti histamine Brompheniramine did not affect capsaicin induced cough though it produced significant drowsiness.

Key words: Brompheniramine, Capsaicin, Cough.

JRMS April 2007; 14(1): 26-29

(5) Introduction action on cough reflex . Non-selective antihistamines Cough is the most common respiratory symptom, are common constituents of over the counter cough and cold remedies and they are claimed to have an anti- however there is no specific anti tussive agent of (2,3,6) proven efficacy(1-4). Opioids are effective anti tussive tussive effect . The mechanism of action of these agents but at their effective doses they also cause non-selective antihistamines is not very well understood; it was thought to be due to their sedative physical dependence, respiratory depression, and (1) gastrointestinal symptoms. The non-narcotic opiate effect, which can suppress most respiratory reflexes . isomer Dextromethorphan is used as anti tussive agent Brompheniramine maleate is a histamine H1-receptor but it has a sedative effect. Persistent non-productive antagonist given by mouth for the symptomatic relief of cough can be a major clinical problem. A selective, hypersensitivity reactions and in pruritic skin disorders. non-sedating anti histamine (terfenadine) has been It is common ingredient of cough and cold preparations. shown to have an effect on cough in seasonal rhinitis It may cause some adverse effects such as sedation and without sinusitis or post nasal drip, but it had no effect antimuscarinic effects. In this study the anti-tussive on induced cough suggesting an indirect mechanism of effect of brompheniramine maleate was examined using the capsaicin challenge. *From the Department of Internal Medicine, Respiratory Medicine Division, King Hussein Medical Center, (KHMC), Amman-Jordan Correspondence should be addressed to Dr. H. El-Khushman, P. O. Box 2399 Amman 11953 Jordan. E-mail: [email protected] Manuscript received October 27, 2005. Accepted January 19, 2006. Methods active treatment, either which they had not received on The study had the approval of the Royal Postgraduate their first visit. Medical School (RPMS) and Hammersmith Hospital Research Ethical Committee. All the subjects gave their Results written informed consent. Verbal consent was obtained The procedures were well tolerated by all subjects. from Healthy employed volunteers recruited from the Capsaicin produced a reproducible cough response RPMS and Hammersmith hospital. Subjects were though individual sensitivity varied. Cough number was excluded if they were smokers, had bronchial asthma, expressed as mean ± confidence interval (CI). Analysis chronic obstructive pulmonary disease, chronic sinusitis of variance was used to compare the differences in the or allergic rhinitis, persistent cough, a clinically two visits. Wilcoxon rank test used to compare the significant history of other drug intake, drug or alcohol number of cough and the level of alertness VAS abuse, or a respiratory tract infection within the between treatments. Results were expressed as previous eight weeks. Subjects were asked if they had treatment (active-placebo) differences (Table I). There taken an investigational drug in the previous three was no significant difference between baseline cough months and they were asked not to drive on the study number on the two study days; 9.9 before days. Brompheniramine and 9.2 before placebo (p=0.34). The study was randomized, double blind, placebo- Mean total cough in response to capsaicin after placebo controlled, cross over design. 12 healthy volunteers (5 pretreatment were similar at 120 and 240 minutes; (8.7, females and seven males), mean age 32 years with a 8.3 respectively). Though there was a slight trend to a range of (23-39) years attended on two separate days decrease of mean total cough after placebo treatment, with a minimum interval of two days between the visits there was no significant difference between mean total and a maximum interval of four weeks from the last cough at 240 minutes 8.3 (6.8-9.8) and baseline 9.2 visit. On the first visit the study was explained and (7.3-11.1) (p=0.43). Mean total cough (CI) at 120 min informed consents were obtained. After history taking on the active day of treatment was 7.7 (5.5-9.8) and physical examination baseline data (height, weight compared to 9.9 (8.2-11.7) at baseline (p=0.49). Mean and lung functions) were collected. Capsaicin cough total cough at 240 min after Brompheniramine challenge was then carried out using doubling treatment was 7.4 (5.1-9.6) compared to 9.9 (8.2-11.7) concentrations starting at 0.500 μM at one minute at baseline (p=0.42). interval according to a standard protocol(7). Subjects The comparison between the two treatment days did inhaled (starting from just below functional residual not show any statistically significant results at both capacity) a single breath of capsaicin from a nebulizer time points (Fig. 1). Oral Brompheniramine did not attached to a breath-activated dosimeter (PK Morgan induce a significant inhibitory effect on capsaicin- Ltd, UK). The output and the mass median diameter of induced cough compared to placebo. Oral the aerosol were 5-7 μl and 3.5-4μ respectively(7). The Brompheniramine induced significant level of number of coughs in response to each concentration drowsiness at 120 min and 240 min following intake; (over the one minute period immediately after each mean VAS (confidence interval) was 31 (14-48) and 40 breath of capsaicin) was recorded by an experienced (21-60) compared to 7 (2-12) and 7 (2-12) after placebo observer. The challenge was stopped when the lowest at 120 and 240 min respectively (p<0.008), (Fig. 2). concentration required to elicit at least 5 coughs (C5) was reached. After a 30 minute delay, two C5 doses of Discussion capsaicin were then administered within 30 seconds This study demonstrated for the first time, that oral apart and the total coughs in the first minute following Brompheniramine has no statistically significant effect the first C5 dose (expected to equal 10) were recorded. on capsaicin-induced cough in normal subjects. After further 5 minutes either Brompheniramine 8 mg Rafferty et al(5) reported that the selective, non- or exactly matched placebo (which was prepared at sedative antihistamine, terfenadine, was effective at Hammersmith Hospital pharmacy) were given orally. reducing cough in seasonal rhinitis patients without Two doses (C5) of capsaicin were then administered sinusitis and post-nasal drip suggesting terfenadine may with cough counting, as at baseline, at 12o and 240 have a direct action on the sensory limb of the cough minutes. At these time points subjects were asked to reflex. quantify the degree of drowsiness they were Studham and Fuller(8) demonstrated that terfenadine experiencing using a 10 cm visual analogue scale does not reduce the cough response to inhaled capsaicin (VAS), this was marked “fully alert” at one end and in normal volunteers suggesting the effect of the non- “extremely sleepy” at the other. In the second visit the selective antihistamines used over the counter remedies procedure was repeated exactly as the first, except that and that of the terfenadine in rhinitis is probably subjects were crossed over to receive either placebo or indirect. The effect in rhinitis is likely to be either through prevention of post-nasal drip, although the alertness did not reflect on cough response measured patients did not report symptom or through inhibition of by capsaicin challenge. The effect of Brompheniramine histamine release in the airways in amounts that did not on capsaicin cough challenge is comparable to that of lead to brnchospasm. It had been postulated that the the non-sedative antihistamine terfendine(8). Cough is anti-tussive effect of the non-selective antihistamine inhibited by morphine and local anesthetics but the could be through inhibition of post-nasal drip in selective, non-sedative antihistamine terfendine was patients with viral infections or through inhibitions of shown to have no effect in a placebo-controlled study in other receptors, such as acetylcholine or 5- normal volunteers(8). hydroxytryptamin receptors(5). The most likely effect of This study showed that the purported anti-tussive these drugs was thought to be through sedation, which action of the non-selective antihistamines might not be will suppress most respiratory reflexes. The hypothesis related to there sedative effect. in this study was that brompheniramine possibly by its Further research is needed in order to provide a better central sedative activity might have an inhibitory effect understanding of cough reflex using the same capsaicin on the sensory afferent arm of the cough reflex(8). cough reflex which stimulates the C-fibers or the Capsaicin by inhalation caused cough and is used as a identification of several new mechanisms which may clinical measure of the sensitivity of the cough reflex. lead to new drugs that target the increased sensitivity of Patients with dry cough are hypersensitive to capsaicin. sensory fibers resulting in exaggerated cough. In this study Brompheniramine had a significant drowsiness effect at both time points of the study in comparison to the baseline as was measured by VAS. Acknowledgment Brompheniramine did not show a statistically Thanks are addressed to Philip Ind, MD, Haleema significant effect on capsaicin-induced cough in Shakur, RN, John Meyers, MD, Respiratory Division, comparison to the baseline at both time points (120 and Hammersmith Hospital, London, UK for their help and 240 min). The measured effect of Brompheniramine on support in conducting this work.

Table I. Cough number and alertness visual analogue scale (VAS) in mm. at different time points Time points Baseline 120 min 240 min Cough VAS Cough VAS Cough VAS Brompheniramine 9.9 8.0 7.7 31 7.4 40 Placebo 9.2 6.7 8.7 7.0 8.3 7.0

Effect of brompheniramine maleate on cough 10 9.5 9 8.5 8 7.5 Mean cough number 7 baseline 120 240 Time points (minutes) Placebo Brompheniramine

Fig. 1. Effect of brompheniramine maleate on cough. Effect of Brompheniramine maleate on alertness

50 40 30 20 10

MeanVAS mm 0 baseline 120 240 Time points (minutes)

Placebo Brompheniramine

Fig. 2. Effect of brompheniramine maleate on alertness

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